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| United States Patent |
5,736,151
|
|
Foster
, et al.
|
April 7, 1998
|
Antibiotic oil suspensions
Abstract
The present invention provides for the inclusion of small amounts of water
in oil suspensions of active drugs, such as ceftiofur hydrochloride of
formula I. The resulting suspensions have improved resuspendability.
Improved resuspendability results in an improved product because less
shaking of the suspension is required before dosing.
##STR1##
| Inventors:
|
Foster; Todd P. (Kalamazoo, MI);
Kiefer; David L. (Alanson, MI)
|
| Assignee:
|
Pharmacia & Upjohn Company (Kalamazoo, MI)
|
| Appl. No.:
|
806584 |
| Filed:
|
December 9, 1996 |
| Current U.S. Class: |
424/423; 514/206 |
| Intern'l Class: |
A61F 002/02; A61K 031/545 |
| Field of Search: |
424/423
514/206
540/227
|
References Cited
U.S. Patent Documents
| 4464367 | Aug., 1984 | Labeeuw.
| |
| 4877782 | Oct., 1989 | Cazers et al. | 514/206.
|
| 4902683 | Feb., 1990 | Amin.
| |
| 4937330 | Jun., 1990 | Sacks.
| |
| 5134137 | Jul., 1992 | Cazers et al. | 514/206.
|
| 5223496 | Jun., 1993 | Cazers et al. | 514/206.
|
Other References
Amin, M.I., et al., J. Pharm. Sci., vol. 76(11):S255 (1976).
Evans, R.A., et al., "Certiofur Hydrochloride, A New Broad-Spectrum
Cephalosporin: Effectiveness Against Induced Haemophilus Pleuropneumoniae
of Growing Swine," Proceedings of the International Pig Veterinary
Society, 10th Congress, Rio de Janeiro, Brazil, p. 94 (1988).
Evans, R.A., et al., "Effectiveness of Ceftiofur Hydrochloride, A New
Broad-Spectrum Cephalosporin, in Treatment of Colibacillosis in Neonatal
Swine," Proceedings of the International Pig Veterinary Society, 10th
Congress, Rio de Janeiro, Brazil, p. 108 (1988).
|
Primary Examiner: Azpuru; Carlos
Attorney, Agent or Firm: Gammill; Martha A.
Claims
We claim:
1. In an oil suspension of ceftiofur hydrochloride in unit dosage form
consisting of an effective amount of ceftiofur hydrochloride, a
biocompatible oil and one or more pharmaceutically acceptable excipients,
the improvement characterized by:
an amount of water which is present at about 0.25% to about 20.20% of the
suspension.
2. The improvement of claim 1 wherein the water is present at about 0.25%
to about 2.20% of the suspension.
3. The improvement of claim 2 wherein the water is present at about 0.30%
to about 0.75% of the suspension.
4. The improvement of claim 3 wherein the water is present at about 0.30%
to about 0.50% of the suspension.
5. In a pharmaceutical composition containing ceftiofur hydrochloride, the
improvement characterized by:
the addition of water.
6. The improvement of claim 5 wherein the water is added in an amount which
is about 0.5 to about 200 mg of water per ml of composition.
7. The improvement of claim 6 wherein the water is added in an amount which
is about 0.5 to about 20 mg of water per ml of composition.
8. The improvement of claim 7 wherein the water is added in an amount which
is about 1 to about 5.5 mg of water per ml of composition.
9. The improvement of claim 8 wherein the water is added in an amount which
is about 1 to about 3 mg of water per ml of composition.
10. A pharmaceutical composition in unit dosage form, which comprises:
a) a drug,
b) a biocompatible oil, and
c) water which is present at about 0.25% to about 20.20% of the
composition.
11. The composition of claim 10 wherein the water is present at about 0.25%
to about 2.20% of the composition.
12. The composition of claim 11 wherein the water is present at about 0.30%
to about 0.75% of the composition.
13. The composition of claim 12 wherein the water is present at about 0.30%
to about 0.50% of the composition.
14. The composition of claim 10 wherein the drug is an antibiotic.
15. The composition of claim 14 wherein the antibiotic is spectinomycin.
16. The composition of claim 10 where the drug is a cephalosporin.
17. The composition of claim 16 wherein the drug is ceftiofur hydrochloride
of formula I
##STR3##
18. The composition of claim 17 wherein the ceftiofur hydrochloride has a
particle size of less than 10 microns and is present at a concentration of
about 50 mg per ml of composition.
19. The composition of claim 10 wherein the oil is selected from the group
consisting of: canola oil, corn oil, cottonseed oil, olive oil, peanut
oil, sesame oil, soybean oil, safflower oil, coconut oil, sunflower oil
and palm oil.
20. The composition of claim 19 wherein the oil is cottonseed oil.
21. The composition of claim 10 which further comprises one or more
pharmaceutically acceptable excipients.
22. The composition of claim 21 wherein the excipients are lecithin and
sorbitan monooleate.
23. The composition of claim 10 wherein the composition is an injectable
oil suspension.
Description
FIELD OF THE INVENTION
The present invention provides for novel pharmaceutical compositions of
active drugs. More particularly, the present invention provides for novel
formulations, such as oil suspensions, of the class of drugs known as
cephalosporins. Most particularly, the present invention provides for
novel oil suspensions of the cephalosporin, ceftiofur hydrochloride, which
have improved properties, such as physical stability (i.e.,
resuspendability).
BACKGROUND OF THE INVENTION
The following five references: W. I. Higuchi, J. Swarbrick, H. F. H. Ho, A.
P. Simonelli and A. Martin, Particle phenomena and coarse dispersions, in
Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing
Company, Easton, Pa., pp. 301-329; M. J. Falkiewicz, Theory of
Suspensions, in Pharmaceutical Dosage Forms: Disperse Systems, Volume 1,
Eds. H. A. Liberman, M. M. Rieger and G. S. Banker, 1988, Marcel Dekker,
New York, N.Y., pp. 13-48; R. A. Nash, Pharmaceutical Suspensions, in
Pharmaceutical Dosage Forms: Disperse Systems, Volume 1, Eds. H. A.
Lieberman, M. M. Rieger and G. S. Banker, 1988, Marcel Dekker, New York,
N.Y., pp. 151-198; N. K. Patel, L. Kennon and R. S. Levinson,
Pharmaceutical Suspensions, in The Theory and Practice of Industrial
Pharmacy, Eds. L. Lachman, H. A. Lieberman and J. L. Kanig, 1986, Lea and
Febiger, Philadelphia, Pa., pp. 479-501; and S. E. Tabibi and C. T.
Rhodes, Disperse Systems, in Modern Pharmaceutics, Third Edition, Revised
and Expanded, Eds. G. S. Banker and C. T. Rhodes, 1996, Marcel Dekker, New
York, N.Y., pp. 310-319; are general textbook discussions on suspensions
and the formulation of physically stable suspensions. Remington's states
at page 313 the major challenge with developing a good suspension is
obtaining physical stability: "The three major problem areas associated
with suspensions are (1) adequate dispersion of the particles in the
vehicle, (2) settling of the dispersed particles, and (3) caking of these
particles in the sediment so as to resist redispersion."
It is generally recognized in the art that controlled particle-to-particle
interaction is a method to produce physically stable suspensions. Coarse
Dispersions: Suspensions, Emulsions and Semisolids, in Physical Pharmacy,
2nd Edition, Eds. A. N. Martin, J. Swarbrick and A. Cammarata, 1969, Henry
Kimpton Publishers, London, England, pp. 522-525; see also E. N. Hiestand,
Theory of Coarse Suspension Formulation, Journal of Pharmaceutical
Sciences, 1964, 53(1): 1-18, especially pages 9-12. Many investigators
refer to this controlled aggregation as "flocculation." The particle
interaction must result in a "loose" particle aggregation so when the
suspension is shaken the particles can separate to some extent and a
uniform dose can be obtained. The particle attraction must be "strong"
enough so particle aggregation does occur. However, the particle
aggregation cannot be so "strong" that the particles will never separate.
Proper particle flocculation allows particles to settle with high
sedimentation volumes and not to pack or cake drug at the bottom of the
container. Physical Pharmacy (cited above) at pages 522-525; E. N.
Hiestand (cited above) at pages 9-12; and W. I. Higuchi et al. (cited
above) at page 315, FIGS. 21-19.
These five general chapters/articles mention several additives which cause
suspensions to flocculate. These flocculating agents include electrolytes,
surfactants and polymers. E. N. Hiestand (cited above) at pages 13-15; and
Physical Pharmacy (cited above) at pages 522-525. Surfactant examples
include polyoxyethylene ethers of mixed partial fatty acid esters of
sorbitol anhydrides (Tweens), the same compounds without the hydrophilic
oxyethylene groups (Spans), higher molecular weight polyethylene glycols
(Carbowaxes) and molecular combinations of polyoxyethylene and
polyoxypropylene (Pluronics). N. K. Patel et al. (cited above) at page
489. Electrolyte examples include sodium chloride, potassium chloride and
calcium salts as well as sulfates, citrates and phosphates. R. A. Nash
(cited above) at page 183. Polymers may include gelatin, natural gums like
tragacanth and xanthan, and cellulose derivatives like sodium
carboxymethylcellulose, hydroxypropylcellulose and
hydroxypropylmethylcellulose. R. A. Nash (cited above) at page 184. None
of the five review articles discuss the importance of water alone in
causing particle-to-particle interaction (or in decreasing
particle-to-particle repulsion) when formulating a pharmaceutical
suspension.
E. N. Hiestand (cited above) at page 14, discloses that, in the paint
industry particularly, oil suspension formulations were prepared using
liquids, such as water, as flocculating agents. Also at page 14, Hiestand
describes the usefulness of water in pharmaceutical suspensions; however,
he does not give any specifics on the drug or the vehicle to be used.
Certainly, he does not mention the use of an oil vehicle. He also states
that a surface-active material (e.g., surfactant) should be included in
the suspension to coat the lyophobic drug surface.
The following four references discuss how small amounts of water in
hydrophobic vehicles (e.g., organic solvents, oils), especially those used
in the paint and printing ink industry, cause flocculation: C. R.
Bloomquist and R. S. Shutt, Fine Particle Suspensions in Organic Liquids,
Industrial and Engineering Chemistry, June, 1940, 32(6): 827-831; F. H.
Rhodes and W. J. Jebens, Studies in the Plasticity of Paints, Journal of
Physical Chemistry, 1930, 35: 383-404; H. R. Kruyt and F. G. Van Selms,
The Influence of a Third Phase on the Rheology of Suspensions, Rec. Trav.
Chim., 1943, 62: 415-426; and A. C. Zettlemoyer, Modern Techniques for
Investigating Interactions with Surfaces, Chem. Rev., 1959, 59: 937-981.
The following more specific prior art references discuss the dispersion of
a drug in oil to produce a suspension: J. Heidt, Injectable Suspensions
Containing Maleic Acid or a Salt Thereof as a Stabilizing Agent, UK Patent
Application 2 105 589 A, published 30 Mar. 1983; A. L. Adjei, S. Borodkin
and R. B. Doyle, Anhydrous Oil-Based Liquid Suspension for Delivering a
Medicament, International Publication Number WO 91/08734, published 27
Jun. 1991; K. Bauer, K. E. Fetting, R. Gonnert, H. Thomas and H. Voege,
New Niclosamide Suspension Formulations, UK Patent 1 527 638, published 4
Oct. 1978; and K. S. E. Su, J. F. Quay, K. M. Capanale and J. F. Stucky,
Nonaqueous Cephalosporin Suspension for Parenteral Administration:
Cefazolin Sodium, Journal of Pharmaceutical Sciences, 1984, 73(11):
1602-1606. None of these references mention the addition of water to oil
formulations or discuss the importance small amounts of water have on
resuspendability.
For example, Heidt claimed a suspension of an active ingredient in a
neutral oil that contains maleic acid or a salt thereof to aid in
resuspendability. The Adjei et al. patent provides general information on
oil suspensions for the administration of drugs which are sensitive to
water or which have an unpalatable taste and explains why certain
ingredients are added to obtain a good suspension product. In referring to
their oil suspension formulation, Adjei et al. states at page 3: "In a
preferred embodiment, the formulation also contains a drying agent to help
bind any residual water that would otherwise degrade the active
therapeutic agent." Bauer et al. obtained a specific patent for
niclosamide (which is an anthelmintic agent) and its salts in an oil-based
suspension. The forms of niclosamide which may be used include its
anhydrous form, its form which contains water of crystallization, as well
as its other salt forms. Su et al. studied the suspension characteristics
of the cephalosporin compound, cefazolin sodium, dispersed in peanut oil
and ethyl oleate (i.e., lipophilic or oleaginous carriers). This article
stated that while water is generally the preferred suspending liquid, some
physiologically active agents such as the cephalosporin antibiotics are
not chemically stable in water-based parenteral pharmaceutical
suspensions. Therefore, according to the article, to achieve a
ready-to-use cephalosporin preparation which can be stored at room
temperature, it is desirable to develop a satisfactory suspension
utilizing a nonaqueous liquid as the suspending medium.
The following two pharmaceutical articles: D. J. A. Crommelin and C. J. de
Blaey, In Vitro Release Studies on Drugs Suspended in Non-Polar Media I.
Release of Sodium Chloride from Suspensions in Liquid Paraffin,
International Journal of Pharmaceutics, 1980, 5:305-316; and D. J. A.
Crommelin and C. J. de Blaey, In Vitro Release Studies on Drugs Suspended
in Non-Polar Media II. The Release of Paracetamol and Chloramphenicol from
Suspensions in Liquid Paraffin, International Journal of Pharmaceutics,
1980, 6:29-42; discussed the addition of small amounts of water (0.01 or
0.05% m/m) to liquid paraffin suspensions (ie. mineral oil) which contain
sodium chloride, paracetamol or chloramphenicol. Water was added to the
oil suspensions to observe the influence of the water on in vitro drug
release. The addition of water to the sodium chloride suspension
significantly enhanced the release rate. The addition of water to the
other two suspensions did not change the release rate. The enhanced
agglomeration of the particles when water was added to any of the three
suspensions was also described.
The Crommelin and de Blaey papers refer to colloidal dispersion research
conducted in the 1960's where the influence of water on dispersions in
nonpolar media was studied. The following two papers: D. N. L. McGown, G.
D. Parfitt and E. Willis, Stability of Non-aqueous Dispersions I. The
Relationship between Surface Potential and Stability in Hydrocarbon Media,
Journal of Colloid Science, 1965, 20:650-664; and A. Kitahara, S. Karasawa
and H. Yamada, The Effect of Water on Electrokinetic Potential and
Stability of Suspensions in Nonpolar Media, Journal of Colloid and
Interface Science, 1967, 25:490-495; examined dispersants like
alpha-alumina, carbon black, copper phthalocynanine green pigment or
barium sulfate in nonpolar solvents such as p-xylene, n-heptane,
cyclohexane or benzene which contain different amounts of surfactants
(e.g. Aerosol TO (sodium di-2-ethylhexyl sulfosuccinate), polyoxyethylene
nonylphenol ether). The amounts of water added were small, normally less
than 400 ppm. These researchers noticed changes in physical stability,
zeta potential and turbidity with different amounts of added water.
However, they also stated that adding water may not result in changes for
all systems as they noted no effect when adding water to carbon black or
barium sulfate in cyclohexane or n-heptane solutions of polyoxyethylene
nonylphenol ether. They also observed the formation of unstable colloidal
dispersions when water was added to these systems in excess of 400 ppm.
Thus, as documented above, the problem in the art has been to develop
pharmaceutically useful suspensions of drugs, which are also physically
stable (i.e., resuspendable). Attempts to solve this problem have not
focused on the addition of water to such suspensions, and in fact, for
cephalosporins, have taught away from its use.
INFORMATION DISCLOSURE
EXCENEL.RTM. Sterile Suspension (ceftiofur hydrochloride) is currently
marketed in the U.S. as a ready-to-use oil suspension product for the
treatment/control of swine bacterial respiratory disease. The ingredients
of this currently marketed formulation are listed below. No water is added
to this formulation, but its ingredients may contain a small amount of
water, as will be described further below. This formulation of ceftiofur
hydrochloride has several disadvantages, such as poor physical stability
(i.e., resuspendability).
Published articles, such as the following, demonstrate the effectiveness of
EXCENEL.RTM. Sterile Suspension as a veterinary antibiotic: "Ceftiofur
Hydrochloride, a New Broad-Spectrum Cephalosporin: Effectiveness Against
Induced-Haemophilus pleuropneumonia of Growing Swine," and "Effectiveness
of Ceftiofur Hydrochloride, a New Broad-Spectrum Cephalosporin, in
Treatment of Colibacillosis in Neonatal Swine," Proceedings of the
International Pig Veterinary Society, 10th Congress, Rio de Janeiro,
Brazil; pp. 94 and 108, respectively (1988). M. I. Amin et al., "Radiation
Sterilization of Suspension Ceftiofur Hydrochloride," J. Pharm. Sci., Vol.
76(11) :S255 (1976), evaluated methods for sterilizing ceftiofur
hydrochloride powder and a suspension formulation containing 3% lecithin
coated ceftiofur hydrochloride.
NAXCEL/EXCENEL.RTM. Sterile Powder (ceftiofur sodium) is also currently
marketed throughout the world for the treatment/control of bovine and
swine bacterial respiratory diseases. This product must be reconstituted
with sterile water before it is injected into the animal.
Amin et al., Crystalline Cephalosporin Hydrohalide Salts, U.S. Pat. No.
4,902,683, 20 Feb. 1990, discloses crystalline hydrochloride and
hydrobromide salts of the cephalosporin antibiotic, ceftiofur, processes
for their manufacture, and pharmaceutical compositions thereof. None of
the compositions disclosed therein teach or suggest the addition of water.
Labeeuw et al., Cephalosporin Derivatives, Process for Preparation Thereof
and Drugs Containing Said Derivatives Usable as Antibiotics, U.S. Pat. No.
4,464,367, 7 Aug. 1984, discloses the cephalosporin antibiotic, ceftiofur,
as well as alkali, alkaline earth and amine salts thereof. This patent
discloses as an apparently prophetic example of a pharmaceutical
composition, ampoules containing the sodium salt of ceftiofur and water
(which would be a solution) for an injectable preparation. However, there
is no indication that such a composition would actually work, and in fact,
it is believed that any such water solution would not be marketable
because of chemical instability.
Dill et al., Conversion of Cephalosporin Hydrohalide Salt to Alkali Metal
Salt, U.S. Pat. No. 4,937,330, 26 Jun. 1990, discloses a process for
making a alkali metal salt of ceftiofur, such as the sodium salt, by the
following steps: a) neutralizing a hydrohalide salt of ceftiofur, such as
the hydrochloride salt, in an aqueous organic solvent, by treating it with
a basic resin; b) filtering the obtained solution to remove the basic
resin; and c) treating the filtrate with a base of an alkali metal.
No where do these references teach or suggest the addition of water to oil
suspensions of cephalosporins, such as ceftiofur hydrochloride.
Furthermore, the addition of water, according to the present invention,
resulted in unexpected improvements in the physcial properties of the
suspension, such as physical stability (i.e., resuspendability) and
shelf-life, as will be described further below.
SUMMARY OF THE INVENTION
The present invention particularly provides:
In an oil suspension of ceftiofur hydrochloride in unit dosage form
consisting of an effective amount of ceftiofur hydrochloride, a
biocompatible oil and one or more pharmaceutically acceptable excipients,
the improvement characterized by: an amount of water which is present at
about 0.25% to about 20.20% of the suspension; preferably, the water is
present at about 0.25% to about 2.20% of the suspension; more preferably,
the water is present at about 0.30% to about 0.75% of the suspension; most
preferably, the water is present at about 0.30% to about 0.50% of the
suspension.
The present invention also provides:
In a pharmaceutical composition containing ceftiofur hydrochloride, the
improvement characterized by: the addition of water. The water is added in
an amount which is about 0.5 to about 200 mg of water per ml of
composition. Preferably, the water is added in an amount which is about
0.5 to about 20 mg of water per ml of composition. More preferably, the
water is added in an amount which is about 1 to about 5.5 mg of water per
ml of composition. Most preferably, the water is added in an amount which
is about 1 to about 3 mg of water per ml of composition.
Finally, the present invention provides:
A pharmaceutical composition in unit dosage form, which comprises:
a) a drug,
b) a biocompatible oil, and
c) water which is present at about 0.25% to about 20.20% of the
composition. Preferably, the water is present at about 0.25% to about
2.20% of the composition. More preferably, the water is present at about
0.30% to about 0.75% of the composition. Most preferably, the water is
present at about 0.30% to about 0.50% of the composition.
The drug in this composition may be an antibiotic such as spectinomycin.
The drug in this composition may also be a cephalosporin such as ceftiofur
hydrochloride. The ceftiofur hydrochloride may have a particle size of
less than 10 microns and may be present at a concentration of about 50 mg
per ml of composition.
The biocompatible oil in this composition may be selected from the group
consisting of: canola oil, corn oil, cottonseed oil, olive oil, peanut
oil, sesame oil, soybean oil, safflower oil, coconut oil, sunflower oil
and palm oil. Cottonseed oil is preferred.
This composition may also contain one or more pharmaceutically acceptable
excipients, such as Phospholipon and sorbitan monooleate.
This composition may be an injectable oil suspension.
In general, the present invention provides an oil suspension of an active
drug which also contains added water.
Drugs which may be formulated in the suspension of the present invention
include the following cephalosporins: First generation (ceftiofur,
cefadroxil, cephalexin, cefazolin); Second generation (cefaclor,
cefuroxime, cefotetan, cefamandole, cefoxitin, cefonicid, cefmetazole);
and Third generation (ceftizoxime, cefoperazone, cefprozil, ceftazidime,
cefotaxime, ceftriaxone, cefixime, cefpodoxime).
Other drugs which may also be formulated in the suspension of the present
invention include the following: Aids Related Complex Therapeutic Agents
(trimethoprim, sulfamethoxazole, zidovudine, dianosine, delavirdine);
Analgesics (aetaminophen, aspirin, ibuprofen, naproxen); Antacids
(aluminum hydroxide, magnesium hydroxide, simethicone); Antibiotics
(spectinomycin, gentamicin, erythromycin, penicillins, quinolones,
sulfonamides, tetracyclines); Antihistamines (hydroxyzine,
diphenhydramine, loratadine); Cardiovascular agents (prazosin, methyldopa,
captopril, propranolol, isosorbide dinitrate, verapamil, furosemide);
Cough and Cold preparations (pseudoephedrine, dextromethorphan,
chlorpheniramine); Dermatologicals (clindamycin, tretinoin,
hydrocortisone, ketoconazole, miconazole); Diabetes agents (glyburide,
chlorpropamide); Diarrhea medications (loperamide); Hormones (estrogens,
growth hormone, methylprednisolone); Hypolipidemics (colestipol,
lovastatin); Nausea medications (meclizine, prochlorperazine); Otic
preparations (neomycin, polymyxin B sulfates); Parkinsonism drugs
(bromocriptine, benztropine); Psycotropics (chlordiazepoxide, diazepam,
triazolam, imipramine).
As described above, the present invention provides for a formulation which
is an oil suspension containing a cephalosporin with added water. More
specifically, the present invention provides for the inclusion of small
amounts of water in oil suspensions of the cephalosporin, ceftiofur,
particularly ceftiofur hydrochloride. The resulting suspensions have
improved resuspendability. Improved resuspendability results in an
improved product because less shaking of the suspension is required before
dosing and allows the product to be stored longer (i.e., longer
shelf-life) because the drug in the product will not settle and compact.
The addition of water may also eliminate the need for including other
formulation agents, such as viscosity-enhancing suspending agents (e.g.,
gelling agents).
The structure of ceftiofur hydrochloride is Formula I as follows:
##STR2##
This compound is a crystalline hydrochloride salt of
7-›2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino)acetamido!-3-›(fur-2-ylcarb
onyl)thiomethyl!-3-cephem-4-carboxylic acid. This cephalosporin free acid
compound is known by the generic name, ceftiofur. Its preparation is
described in U.S. Pat. No. 4,902,683, Amin et al., 20 Feb. 1990, which is
hereby incorporated by reference.
The amount of water which is to be added to obtain the suspension of the
present invention ranges from about 0.5 to about 200 mg of water per ml of
formulation; preferably about 0.5 to about 20 mg of water per ml of
formulation is added; more preferably about 1 to about 5.5 mg of water per
ml of formulation is added; most preferably, about 1 to about 3 mg of
water per ml of formulation is added.
As described above, the formulation of the present invention consists of an
active drug ingredient, such as the cephalosporin ceftiofur hydrochloride,
a biocompatible oil and water. The biocompatible oil is composed
essentially of triglycerides, which are long chain fatty acid esters of
glycerol, or mixtures of triglycerides and fatty acids. Trihydroxy,
dihydroxy, monohydroxy or even polyhydroxy compounds may be substituted
for the glycerol. The oils may be of vegetable, animal or synthetic
origin. Preferred oils include canola, corn, cottonseed, olive, peanut,
sesame, soybean, safflower, coconut, sunflower, and palm. The especially
preferred oil is cottonseed oil.
The concentration of the cephalosporin in the formulation of the present
invention may vary between about 1 mg/ml to 500 mg/ml. Preferably, for
ceftiofur hydrochloride, the concentration is about 50 mg/ml. In general,
the upper limit on the concentration is determined by when the oil
composition becomes too viscous to syringe.
The suspension of the present invention may also contain other
pharmaceutically acceptable excipients normally included in such
suspensions, for example, suspending agents, preservatives, wetting agents
or flocculating agents, if desired. Suspending agents, such as gums (e.g.,
acacia, carrageenan, sodium alginate and tragacanth), cellulosics (e.g.,
sodium carboxymethylcellulose, microcrystalline cellulose, and
hydroxyethylcellulose), and clays (e.g., bentonite and colloidal magnesium
aluminum) may be included. Preservatives, such as methyl and propyl
paraben, benzyl alcohol, chlorobutanol and thimerosal may be added.
Wetting agents such as anionic (e.g., docusate sodium and sodium lauryl
sulfate) and nonionic (polysorbates, polyoxamers, octoxynol-9) surfactants
may be used. Thickeners, such as gelatin, natural gums and cellulose
derivatives (such as those listed above as suspending agents) may be
added. Buffers, such as citrate and phosphate buffering agents, may be
included, as well as osmotic agents, such as sodium chloride and mannitol.
For oral suspensions, additional agents may be used, such as the
following: flavoring agents, sweeteners (e.g., mannitol, sucrose, sorbitol
and dextrose), colorants and fragrances. Particularly, for the
formulations of the present invention, excipients such as sorbitan
monooleate (which may be used as a wetting agent) and Phospholipon (which
may be used as a dispersant) may be added.
The suspension of the present invention may be prepared by any method known
in the art for the preparation of injectable suspensions. All such methods
involve the active ingredient being present in a suitable solid form and
suspension thereof in a liquid vehicle. However, if the formulation
contains Phospholipon, the Phospholipon may be added via a heating and
cooling step, which may be considered different from a typical suspension
manufacture.
The preparation of a 5 L batch of the ceftiofur hydrochloride suspension of
the present invention is shown in EXAMPLE 1 below. Micronized ceftiofur
HCl, which consists of particles with a median geometric mean below 10
microns, may be preferably used. However, as one skilled in the art
realizes, the particle size may vary above and below the preferred size
depending on the cephalosporin, the biocompatible oil and any other
ingredients used in the composition. In fact, nonmicronized drug may be
used in some embodiments.
A manufacturing facility suitable for producing sterile products must be
used if one is making this composition as an injectable for commercial
use. Also, all manufacturing equipment and packaging components should be
sterilized when making the suspension for administration by injection.
The suspension of the present invention, which contains ceftiofur
hydrochloride as its active ingredient, is useful as an antibiotic to cure
bacterial infections of animals, such as livestock and poultry. Ceftiofur
hydrochloride is a broad spectrum cephalosporin antibiotic active against
gram-positive and gram-negative bacteria, including
beta-lactamase-producing strains. For animals, it is effective in swine
against a variety of diseases, such as diarrhea, pneumonia (Actinobacillus
pleuropneumoniae, Pasteurella multocida, Salmonella choleraesuis and
Streptococcus suis type 2), transmissible gastro enteritos; avian
pneumonia (mycoplasma, haemophilus) and Marek's diseases; and is effective
in cattle against a variety of diseases, such as bovine diarrhea,
pneumonia and mastitis.
The effective amount of this antibiotic to be used will vary depending on
the species, age and/or weight of the animal being treated. It could vary
between about 0.1 and 100 mg/kg. For example, when treating swine
bacterial respiratory disease (swine bacterial pneumonia, SBP), the dose
may range between about 3 and 5 mg/kg given once daily for three
consecutive days.
Also, the concentration of the oil composition will depend on the species
to be treated and the dose of antibiotic required. For example, when
treating SBP at a dose of 3 mg/kg, a 50 mg/mL concentration solution is
preferred. One injection of 1.0 mL will provide the required composition
for each 22-37 pound body weight.
The routes of administration include oral and parenteral, such as
subcutaneous and intramuscular. The preferred route of administration in
livestock is subcutaneous. However, other parenteral routes of
administration, like intramuscular, may be used.
Furthermore, those skilled in the art would know how to formulate the
composition of the present invention, using pharmaceutically acceptable
excipients, into appropriate unit dosage forms. The term "unit dosage
form" refers to physically discrete units suitable as unitary dosages for
mammalian subjects, each unit containing as the essential active
ingredient a predetermined quantity of the drug of this invention with the
required pharmaceutical means which adapt said ingredient for systemic
administration. Examples of such dosage forms include oral formulations,
such as tablets or capsules, or parenteral formulations, such as
injectable suspensions.
Additional information on the dosage and mode of administration of the
antibiotic ceftiofur hydrochloride is contained in U.S. Pat. No.
4,902,683, which is hereby incorporated by reference herein.
In the present invention, the addition of water to the ceftiofur
hydrochloride suspension causes the particles to flocculate and settle in
the suspension, resulting in an improved and pharmaceutically useful
suspension. This enhanced flocculation (i.e., aggregation) observed when
adding small amounts of water to ceftiofur oil suspensions results in a
suspension that resuspends more easily. The improved properties of the
suspension of the present invention is further detailed in EXAMPLE 2
below.
The currently marketed formulation of ceftiofur hydrochloride, known as
EXCENEL.RTM. Sterile Suspension, contains the following ingredients per
mL:
______________________________________
Ceftiofur HCl micronized
50 mg*
Phospholipon 90-H (lecithin)
0.50 mg
Sorbitan monooleate NF
1.50 mg
Cottonseed oil NF enough to make 1 mL
______________________________________
*This is the amount of ceftiofur activity.
No water is added to this formulation; however, water may be present in its
other ingredients (e.g., bulk ceftiofur hydrochloride and cottonseed oil)
and/or due to environmental conditions. As currently manufactured and
sold, the total amount of water which has been measured as being present
in this formulation ranges from about 0.1% to 0.2% (which is about 1 to 2
mg of water per ml of formulation).
A ceftiofur hydrochloride formulation of the present invention has the
following ingredients:
______________________________________
Ceftiofur HCl micronized
50 mg*
Water for Injection, USP
20 mg
Cottonseed oil NF enough to make 1 mL
______________________________________
*This is the amount of ceftiofur activity.
An important difference between the formulation of the present invention
and the formulation that is currently marketed is that water is added to
the formulation of the present invention--in addition to that which may
already be present, as noted above. Assuming the currently marketed
formulation contains about 2.0 mg of water per ml of formulation (which is
the upper limit which has been identified, as noted above), the amount of
water which is added to obtain the suspension of the present invention
ranges from about 0.5 to about 200 mg of water per ml of formulation;
preferably about 0.5 to about 20 mg of water per ml of formulation is
added; more preferably about 1 to about 5.5 mg of water per ml of
formulation is added; most preferably, about 1 to about 3 mg of water per
ml of formulation is added.
Thus, the resulting formulation of the present invention will have a total
amount of water of about 0.25% to about 20.20% (which is about 2.5 to
about 202.0 mg of water per ml of formulation). Preferably, the resulting
formulation of the present invention will have a total amount of water of
about 0.25% to about 2.20% (which is about 2.5 to about 22.0 mg of water
per ml of formulation). More preferably, it will have a total amount of
water of about 0.30% to about 0.75% (which is about 3.0 to about 7.5 mg of
water per ml of formulation). Most preferably, it will have a total amount
of water of about 0.30% to about 0.50% (which is about 3.0 to about 5.0 mg
of water per ml of formulation).
Surprisingly and unexpectedly, the addition of this small amount of water
results in a ceftiofur hydrochloride formulation with substantially
improved properties, as documented below.
A preferred ceftiofur hydrochloride formulation of the present invention
has the following ingredients:
______________________________________
Ceftiofur HCl micronized
50 mg*
Phospholipon 90-H (lecithin)
0.50 mg
Sorbitan monooleate NF
1.50 mg
Water for Injection, USP
2.50 mg
Cottonseed oil NF enough to make 1 mL
______________________________________
*This is the amount of ceftiofur activity.
The unexpected differences in the properties of these two formulations are
documented in EXAMPLE 2 below.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE 1
Ceftiofur Hydrochloride Oil Suspension--Water Added (5 L Batch)
The ingredients listed in Table 1 are secured:
TABLE 1
______________________________________
Amounts Required for a 5 L Batch
Ingredient Amount Amount per mL
______________________________________
Ceftiofur HCl micronized
0.258 kg*
50 mg
Phospholipon-90H 0.25 g 0.5 mg
Sorbitan monooleate NF
0.75 g 1.5 mg
Water for Injection, USP
1.25 g 2.5 mg
Cottonseed Oil q.s. to 5 L
q.s. to 1 mL
______________________________________
*The amount is of active ceftiofur taking into consideration the salt.
Assumes 100% potent ceftiofur HCl with 3.2% w/w of the weight accounting
for the HCl. MW of ceftiofur HCl is 560.0.
The required weight or volume of oil is placed into a glass or stainless
steel vessel. (See Table 1 for the amounts required for a 5 L batch.) For
a 5 L batch, 4.5 L of cottonseed oil is used to begin. The oil is heated
to above 100.degree. C. and the required amount of Phospholipon (lecithin)
is added and stirred until dissolved. The time required for the
Phospholipon (lecithin) to dissolve depends on the temperature, mixing,
and size of the batch. It normally dissolves within 1 to 60 minutes. The
oil containing the Phospholipon is then cooled. Once cooled the sorbitan
monooleate is added and mixed. Next the ceftiofur HCl is added followed by
mixing of 1 to 120 minutes. The length of mixing depends on the batch
size, size of mixer and speed of mixing. Water is added and the suspension
is mixed for 1 to 60 minutes.
The suspension is stored in the original manufacturing vessel as long as
mixing continues to keep the drug suspended. It is then filled into vials
using standard vial filling equipment. The vials are then closed with a
stopper, capped, labeled and boxed.
EXAMPLE 2
Comparison of the Currently Marketed Formulation of Ceftiofur Hydrochloride
and Formulations of the Present Invention
A. Resuspendability or Physical Stability
One of the most important differences observed between the fomulations was
the greater physical stability or resuspendability when water was added to
the formulation. Shown in FIG. 1 is a plot of resuspendability compared to
the water content of various ceftiofur HCl suspensions.
It is clear from this figure that as the water content increased, the
suspension resuspended better. The resuspendability of suspensions with
lower water content was poor or, at best, variable. It was not until the
water content was increased that consistently more resuspendable
suspensions were achieved. More specific physical stability comparisons
are shown in the next section.
Several other differences were observed when increasing the water content
of the suspension. All these differences help explain why greater physical
stability was observed when adding water: First, sedimentation volumes
were greater, and the sedimentation rates faster when water was added. The
sedimentation volume is the height of the sediment when compared to the
height when the suspension is fully resuspended. Larger sedimentation
volumes typically are associated with a suspension that resuspends better.
Less packaging of the sediment occurs making it easier to resuspend (i.e.,
less energy needs to be put into the system via shaking).
Second, the faster settling rate indicates the particles are interacting to
create a flocculated system. A flocculated suspension typically resuspends
better then a nonflocculated suspension. The flocs that form will be
larger then the original particles so they settle faster. But, because
they interact with themselves and other flocs, they will not settle to
such low sedimentation volumes. Thus, they are easier to resuspend. The
addition of water to the formulation of the present invention caused
flocculation and faster sedimentation rates were observed.
Also, flocculation was observed with particle size data. Larger measured
particles were observed as the water content of the suspension increased.
Furthermore, photomicrographs were taken showing the particles interacting
to create larger flocs.
Finally, rheology differences were noted when adding water to the
formulation. The rheology, or flow characteristics, changed from Newtonian
to non-Newtonian with added water. The plastic systems found with added
water indicate a structure was formed in the water-added suspensions. This
added structure again indicates a flocculated system which will have
improved resuspendability.
In summary, all of the differences found between the suspensions with and
without added water indicate that physical stability will be better with
the water-added formulation.
B. Chemical Stability and Shelf-life
The stability of suspensions, and ultimately their shelf-life, are based on
both chemical and physical stability. The chemical stability is assessed
to insure that the product does not become subpotent during use. The
chemical stability of the current formulation (ie. non-water-added
formulation) has been studied extensively. For example, shown in Table 2
is the stability through 3 years for 3 different batches of the current
suspension.
TABLE 2
______________________________________
Chemical Stability of a 50 mg/mL Ceftiofur HCl Suspension with No
Additional Water Added when Stored at 25.degree. C.
Potency in mg/mL .+-. standard deviation
Time, months
Lot A Lot B Lot C
______________________________________
0 49.8 .+-. 0.7
51.1 .+-. 0.5
50.5 .+-. 0.3
3 48.4 .+-. 1.3
49.4 .+-. 1.6
48.4 .+-. 0.4
6 48.1 .+-. 0.7
48.8 .+-. 1.2
48.6 .+-. 0.7
12 49.1 .+-. 0.4
50.2 .+-. 0.3
50.1 .+-. 0.3
18 46.5 .+-. 1.4
48.5 .+-. 0.7
48.5 .+-. 0.9
24 46.8 .+-. 4.2
48.8 .+-. 0.6
49.2 .+-. 2.7
36 49.1 .+-. 0.8
49.5 .+-. 0.4
48.6 .+-. 0.7
______________________________________
Usually pharmaceutical products are allowed to decrease 10% in potency
during their shelf-life. Table 2 shows the current suspension is
chemically stable even out to three years when stored at room
temperatures.
The chemical stability has not been assessed for as long with the
formulation of the present invention containing additional water. Shown in
Table 3 is the comparison of two batches that were made identically except
for the amount of water added. Similarly, Table 4 shows another comparison
of two batches that only varied in water content.
TABLE 3
______________________________________
Comparison of Chemical Stability of Two Batches with Different Water
Contents when Stored at 25.degree. C.
Potency as a percent of label .+-. standard deviation
Time, months
Lot D (0.20% total water)
Lot E (0.39% total water)
______________________________________
0 103.2 .+-. 0.5 102.2 .+-. 0.2
2 103.2 .+-. 0.4 101.6 .+-. 0.0
4 103.6 .+-. 0.3 103.3 .+-. 1.3
6 103.7 .+-. 0.4 103.0 .+-. 0.2
______________________________________
TABLE 4
______________________________________
Comparison of Chemical Stability of Two Batches with Different Water
Contents when Stored at 25.degree. C.
Potency as a percent of label .+-. standard deviation
Time, months
Lot F (0.14% total water)
Lot G (0.67% total water)
______________________________________
0 104.5 .+-. 0.3 103.4 .+-. 0.6
2 104.6 .+-. 1.7 103.1 .+-. 0.1
4 105.5 .+-. 0.7 105.4 .+-. 0.5
6 103.5 .+-. 0.5 102.9 .+-. 0.1
______________________________________
Both Tables 3 and 4 show the suspension to be chemically stable. No
difference was observed in chemical stability even with high water
content. Thus, contrary to what may be expected, the addition of water did
not adversely affect the chemical stability of the suspension. Additional
stability data which was obtained at accelerated temperatures shows no
difference in stability with higher water content.
C: Physical Stability
Physical stability is just as important as chemical stability. If the
product does not resuspend adequately when shaken, the dose will be
incorrect. With incomplete resuspension when shaken, the initial doses
removed will be subpotent. This occurs because drug remains at the bottom
of the vial preventing the correct concentration of the suspension when
agitated. If part of the product is removed at a concentration
significantly less then the labeled concentration, doses removed when the
vial contains less product could become superpotent. This happens when
further agitation removes drug from the bottom of the container and it is
dispersed in the smaller volume of liquid.
The current formulation (ie. no water added) needs to be shaken, sometimes
up to 60 seconds, before it becomes fully resuspended as shown in Table 5:
TABLE 5
______________________________________
Physical Stability of a 50 mg/mL Ceftiofur HCl Suspension with No
Additional Water Added when Stored at 25.degree. C.
Time Required to Fully Resuspend, Seconds
Time, months
Lot A Lot B Lot C
______________________________________
0 10-20 10 10
3 30-40 10-20 20-30
6 30 10 20
12 50-60 20-30 40-50
18 40-60 20 30
24 50-60 60 40-60
36 60 40-50 60
______________________________________
It has been found that the addition of water improves the resuspendability
characteristics of the suspension. A sensitive method for monitoring
resuspendability is to use a 10-second mechanical shake assay. In this
test, a vial is shaken for 10 seconds using a mechanical arm. A sample is
removed from the suspension 2 cm below the liquid/air interface and
assayed for the amount of drug. Shown in Tables 6 and 7 below are batches
produced by identical methods except for the amount of water:
TABLE 6
______________________________________
Comparison of Physical Stability of Two Batches with Different Water
Contents using a 10-Second Mechanical Shake Test
Potency as a percent of label .+-. standard deviation
Time, months
Lot D (0.20% total water)
Lot E (0.39% total water)
______________________________________
0 82 .+-. 4 99 .+-. 2
2 72 .+-. 40 98 .+-. 1
4 48 .+-. 7 97 .+-. 2
6 49 .+-. 3 96 .+-. 1
______________________________________
TABLE 7
______________________________________
Comparison of Physical Stability of Two Batches with Different Water
Contents using a 10-Second Mechanical Shake Test
Potency as a percent of label .+-. standard deviation
Time, months
Lot F (0.14% total water)
Lot G (0.67% total water)
______________________________________
0 79 .+-. 5 104 .+-. 1
2 32 .+-. 21 101 .+-. 2
4 58 .+-. 16 102 .+-. 3
6 67 .+-. 27 95 .+-. 2
______________________________________
As the data from these tables shows, the increased water content improved
resuspendability. The formulations with higher water concentrations were
closer to the theoretical 100% of label and had less vial-to-vial
variability (ie. tighter standard deviations).
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a plot of resuspendability compared to the water content of
various ceftiofur HCl suspensions.
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